Cyclin D1, glutathione S-transferase, and cytochrome P450 genotypes and outcome in patients with upper aerodigestive tract cancers: assessment of the importance of individual genes using multivariate analysis.

GST, CYP, and CCND1 genotypes have been associated with outcome in several cancers. Accordingly, we have examined, in patients with one squamous cell carcinoma (SCC) of the head and neck, associations between GSTM1, GSTT1, GSTM3, GSTP1, CYP2D6, CYP1A1, CYP2E1, and CCND1 genotypes and the outcome parameters, tumor extension, histological grade, and presence of nodes. We used logistic regression to study, first, each gene individually and, second, in a step-wise model that included all of the genes. Different genes were associated with each outcome parameter. Thus, GSTT1 null was associated with T3/T4 lesions in the oral cavity/pharyngeal (P = 0.029), but not laryngeal, SCC cases. GSTT1 null was also associated with histological differentiation (G3) in the oral cavity/pharyngeal, but not laryngeal, SCC cases, although this association only approached significance (P = 0.069). CCND1 GG was associated with G3 tumors in the oral cavity/pharyngeal (P = 0.011), but not laryngeal, SCC cases. The combination of GSTT1 null/CCND1 GG was also associated with G3 tumors. CYP2D6 PM and HET were associated with lymph node involvement in the laryngeal, but not oral/pharynx, SCC cases. Genes that were individually associated with outcome were also associated with the parameter in the step-wise routine. The GSTT1 null frequency was greater in 39 patients with second primary tumors than in those with one lesion (P = 0.014). The data demonstrate site-dependent associations between GSTT1 null, CCND1 GG, and CYP2D6 PM and tumor extension, differentiation, and nodes.

Alpha, mu and pi class glutathione S-transferases in human synovium and cultured synovial fibroblasts: effects of interleukin-1 alpha, hydrogen peroxide and inhibition of eicosanoid synthesis.

We describe expression of alpha, mu and pi class glutathione S-transferase (GST) and, CuZn- and Mn superoxide dismutase (SOD) in human synovium and cultured synovial fibroblasts. Immunohistochemical and immunoblotting studies showed synovium and cultured cells expressed pi GST and both isoforms of SOD. Cellular localisation was largely perinuclear. No expression of alpha or mu GST was detected even though polymerase chain reaction analysis showed 4/6 subjects had positive genotypes at the polymorphic, mu class GSTM1 locus. Incubation of cultured synovial fibroblasts with H2O2, IL-1 alpha and the cyclooxygenase and lipoxygenase inhibitor, Tenidap, did not induce expression of alpha, mu or pi GST though treatment with IL-1 alpha caused a marked increase in the expression of Mn SOD.

The therapeutic response to D-penicillamine in rheumatoid arthritis: influence of glutathione S-transferase polymorphisms.

OBJECTIVES: To investigate whether the therapeutic response of rheumatoid arthritis (RA) patients to D-penicillamine is associated with polymorphisms in genes of the glutathione S-transferase (GST) supergene family. METHODS: Disease activity in 81 patients with RA treated with D-penicillamine monotherapy was assessed using the Stoke Index, a validated index of disease activity, prior to treatment and at 6 months. GST typing was performed using a polymerase chain reaction-based approach and a logistic regression model was used to investigate any possible association between the therapeutic response to D-penicillamine and the GST genotype. RESULTS: A poor therapeutic response was associated with the GSTM1 null genotype [odds ratio (OR) 3.94], and in particular with the GSTM1*0/GSTM3*A haplotype (OR 7.63). CONCLUSIONS: Our results suggest that GST polymorphisms may influence the response to D-penicillamine in RA, and that patients in possession of the GSTM1*0/GSTM3*A haplotype are significantly less likely to show a beneficial response to the drug.

Association of polymorphism in glutathione S-transferase loci with susceptibility and outcome in rheumatoid arthritis: comparison with the shared epitope.

OBJECTIVE: To determine whether glutathione S-transferase GSTM1, GSTM3, GSTT1, and GSTP1 genotypes influence susceptibility or outcome in rheumatoid arthritis (RA). METHODS: 277 RA patients were compared with 577 controls to examine any associations between GST genotypes and susceptibility to RA. The effect of genotypes on outcome (Larsen and functional scores) and time integrated acute phase responses (erythrocyte sedimentation rate and C reactive protein) was assessed in 122 patients with disease duration of 5-10 years. GST and HLA-DRB1 genotypes were determined using polymerase chain reaction based assays. Data were analysed using multiple regression analysis with correction for age, sex, disease duration, and the DRB1 associated shared epitope (SE) and rheumatoid factor (RF) positivity where appropriate. RESULTS: The GSTM1*A/*B genotype was less common in RA cases (3 of 276) than in controls (22 of 591) (exact p = 0.047), though significance was lost when adjustment was made for multiple comparisons. The Larsen score was higher (p = 0.039) in the GSTM1 null patients (89.9) than those with other GSTM1 genotypes (74.7), and this was independent of the SE. Again, correction for multiple testing resulted in loss of significance. The difference in Larsen scores between patients homozygous or negative for the SE (87.9 v 74.3) was similar to that between GSTM1 null and non-null patients. No associations between GSTM3 or GSTT1 genotypes and disease markers were identified although the association between GSTP1*B/*B and Larsen score approached significance (p = 0.096). CONCLUSION: It is proposed that certain GSTs may influence susceptibility and radiological progression in RA and that this is independent of the effect of the HLA-DRB1 associated SE. The mechanism for this effect is presumed to be because of differences in the ability of various GST enzymes to utilise the cytotoxic products of oxidant stress. Although significance was lost after correction for multiple testing, the data indicate that further studies may be of value in RA to determine the influence of the GST and other genes involved in cellular protection against oxidative stress.